In cystic fibrosis (CF), a defect in mucosal defenses leads to airway colonization with bacteria, inflammation, remodeling, and tissue destruction. The disease is progressive and life limiting. Recent studies indicate that loss of CFTR function reduces bicarbonate permeability across the airway epithelium and lowers the pH of airway surface liquid (ASL), impairing the function of secreted host defense factors. This may be among the earliest events favoring colonization. Respiratory viral infections may also contribute to development of lung disease in infants and children with CF. Epidemiologic data indicate that respiratory virus infections cause prolonged symptoms in children with CF, induce exacerbations, and enhance bacterial colonization. While clinical studies and limited in vitro data suggest the possibility of altered responses to viruses in CF, this is an experimentally difficult problem to study in humans. Our central hypothesis is that virus infections contribute to disease onset and progression in CF. The CF pig model manifests a respiratory tract host defect at birth and spontaneously develops lung disease with many similarities to human infants with CF. The objective of. our studies is to use this model to investigate the contribution of virus infections to early CF lung disease. We will test our central hypothesis, using model virus infections and by pursuing the following three specific aims: Aim 1. Do CFTR dependent changes in ASL environment allow respiratory viruses to infect airway epitheliamore readily? Aim 2. Do changes in interferon induction and responsiveness enhance respiratory virus infections in CF? Aim 3. Does CF alter the resolution phase ofthe response to respiratory virus infections? Leveraging the porcine CF model to study CF and non-CF responses to viral infections in vitro and in vivo is a novel approach to investigate human disease mechanisms. These complementary strategies should provide new insights into the early steps in CF lung disease pathogenesis that will inform future therapeutic strategies.